The unfolded protein response (UPR) allows cells to respond to stress conditions including nutrient deprivation. The glucose regulated protein GRP78/BiP, an endoplasmic reticulum (ER) chaperone with anti- apoptotic properties, represents a major pro-survival component of the UPR. Aging is known to cause decline in both protein levels and activities of ER chaperones, including GRP78, thereby decreasing the protein folding capacity, creating ER stress. Aging also impairs other protective effects of ER stress signaling, leading to accumulation of malfolded proteins in the ER, triggering apoptosis and age-related pathology. Furthermore, ER stress reduction has been proposed to be a central factor in life span extension in model organisms, and protection conferred by dietary restriction and short term starvation against DNA damaging and cytotoxic stress may be mediated in part by reduction of ER stress. In collaboration with Longo (Project 1) and Cohen (Project 2), we discovered novel links between starvation, dietary restriction, IGF-I signaling, and GRP78. Our preliminary results revealed that both short term starvation and long term dietary restriction decrease GRP78 expression in mice and cells and that GRP78 is both an upstream regulator and a downstream target ofthe IGF-1R/PI3K/AKT pathway. This led us to propose that reduction in ER stress plays pivotal role in the effects of dietary restriction and reduced IGF-1 in stress resistance and aging. Here, we will test the hypothesis that chronic dietary restriction or acute starvation reduces lGF-1 production, leading to lowering of ER stress, thus increasing protection against toxins and survival. We also propose that dietary restriction and reduced lGF-1 will not cause a reduction in ER stress but cause a reduction in the anti-ER stress protein GRP78 in tumors, thus creating a tumor-specific effect. In aim 1, we will investigate the role of GRP78 and UPR on the effects of dietary restriction and aging, utilizing mouse models with altered GRP78 level. Aim 2 will determine the link between pro-aging pathways and GRP78 and utilize the GHRKO mouse model to test the interdependence of GRP78 and IGF-1 on stress resistance, longevity, and age-dependent diseases in vivo. Finally, Aim 3 will test directly the role of GRP78 on acquisition of resistance to cytotoxic agents and aging in mice, through creation of transgenic mouse model with conditional overexpression of GRP78 in parallel to analogous yeast studies in Project 1. This collaborative work will provide new insights into the link between interventions and pathways well established to affect aging and age-related diseases, ER stress, and the major protein GRP78 that protects against it. Thus, this work not only addresses fundamental mechanisms but also has direct clinical relevance.